Identification of a Novel TRPM8 Agonist from Nutmeg: A Promising Cooling Compound.

The transient receptor potential melastatin 8 (TRPM8) ion channel is the primary receptor for innocuous cold stimuli (<28 °C) in humans. TRPM8 agonists such as -(-)-menthol are widely used as flavors and additives to impart briskness, in addition to medicinal uses for inflammation and pain. Though various natural and synthetic agonists have been explored, only few natural compounds are known. We report herein the identification and characterization of the novel neolignan agonist - and -Δ-7-ethoxy-4-hydroxy-3,3',5'-trimethoxy-8--4'-neolignan () with an EC of 0.332 μM, which was isolated from a well-known spice, nutmeg ( Houtt.). Structure activity relationships are also disclosed, showing that the 7--menthoxy derivative is the most potent agonist (EC = 11 nM). The combination of and -(-)-menthol has an additive effect, suggesting that neolignan compounds interact with TRPM8 at different sites from those of -(-)-menthol.